Benzocycloalkylaminopyridinamines and related compounds as topical antiinflammatory agents for the treatment of skin disorders

ABSTRACT

There are described compounds of the formula, ##STR1## where R is hydrogen, loweralkyl, arylloweralkyl or loweralkylcarbonyl; 
     k is 0 or 1; 
     m is 1,2 or 3; 
     k+m is 2 or 3; and 
     n is 0 or 1; 
     which compounds are useful as topical antiinflammatory agents for the treatment of various dermatoses.

The present invention relates to compounds of Formula I, ##STR2## whereR is hydrogen, loweralkyl, arylloweralkyl or loweralkylcarbonyl;

k is 0 or 1;

m is 1, 2 or 3;

k+m is 2 or 3; and

n is 0 or 1;

which compounds are useful as topical antinflammatory agents for thetreatment of various dermatoses including, for example, exogenousdermatitides (e.g. sunburn, photoallrtgic drmatitis, urticaria, contactdermatitis, allergic dermatitis), endogenous dermatitides (e.g. atopicdermatitis, seborrheic dermatitis, nummular dermatitis), dermatitides ofunknown etiology (e.g. generalized exfoliative dermatitis), and othercutaneous disorders with an inflammatory component (e.g. psoriasis).

Also included within the scope of this invention are compounds ofFormula II where k, m and n are as defined above, which are useful forthe same dermatological applications as mentioned above and also asdirect precursors of the compounds of Formula I. ##STR3##

Unless otherwise stated or indicated, the following definitions shallapply throughout the specification and the appended claims.

The term loweralkyl shall mean a straight or branched alkyl group havingfrom 1 to 6 carbon atoms. Examples of said loweralkyl include methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl andstraight- and branched-chain pentyl and hexyl.

The term halogen shall means fluorine, chlorine, bromine or iodine.

The term aryl shall means a phenyl group optionally mono-substitutedwith a loweralkyl, loweralkoxy, halogen or trifluoromethyl group.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo, optical, geometrical andtautomeric isomers where such isomers exist.

The compounds of this invention are prepared by utilizing one or more ofthe synthetic steps described below.

Throughout the description of the synthetic steps, the notations R, k,m, and n shall have the respective meaning given above unless otherwisestated or indicated, and other notations shall have the respectivemeanings defined in their first appearances unless otherwise stated orindicated.

STEP A

A compound of Formula II where Hal is F or Cl, preferably F, is allowedto react with a compound of Formula IV to afford a compound of FormulaII. ##STR4##

this reaction is typically conducted in a suitable solvent such asethanol, dimethylformamide, diemthylsulfoxide or N-methylpyrrolidone ata temperature of about 0 to 150° C.

3-Fluoro-4-nitropyridine-1-oxide, which belongs to the group ofcompounds of Formula III, is disclosed in Talik and Talik, RocznikiChemii, Volume 38, 777 (1964). 4-chloro-3-nitropyridine, which alsobelongs to the group of compounds of Formula III, is disclosed in Talikand Talik, Roczniki Chemii, Volume 43, 923 (1969).

STEP B

A compound of Formula IIa is selectively hydrogenated to afford acompound of Formula V. ##STR5##

This selective hydrogenation is typically conducted with the aid of asuitable catalyst such as Pd/C or PtO₂ and a suitable medium such asethanol at a temperature of about 20 to 100° C.

STEP C

Compound IIa is catalytically hydrogenated in a manner similar to theone described in STEP B above, except that a longer reaction period orhigher reaction temperature is preferably employed, to afford a compoundof Formula VI. ##STR6##

Instead of using compounds IIa in the above reaction, one can also usecompound V and conduct the hydrogenation is substantially the samemanner as described above to obtain compound VI.

STEP D

A compound of Formula VII obtained from STEP B or C is allowed to reactwith a compound of the formula, R-Hal, where R is loweralkyl,arylloweralkyl or loweralkylcarbonyl and Hal is bromine or chlorine, ina routine manner known to the art to afford a compound of Formula I.##STR7##

Compounds of Formula I and Formula II according to this invention areuseful as topical agents for the treatment of various skin disorderssuch as those mentioned earlier. The dermatological activates of thecompounds of this invention were ascertained with reference to thefollowing methods.

DERMATOLOGICAL TEST METHODS Phospholipase A₂ -induced Paw Edema (PIPE)A₂ -induced paw edema in male Wistar rats (100-125 g) was measured. PLA₂(3 units/paw) alone or with 0.1 M of the test compound was injected inthe subplantar region of the rat left hind paw. Immediately subsequentto the injection and at two hours post administration the paw wasimmersed in a mercury bath, and paw displacement was measured on arecorder via a transducer. (Standard: hydrocortisone ED₅₀₌₀.46 M). SeeGiessler, A. J. et. al., Agents and Actions, Vol. 10, Trends inInflammation Research (1981), p. 195. In Vitro Phospholipase A₂ Assay(PLA₂)

The ability of a compound to modulate PLA₂ activity (clevage of ¹⁴-dipalmitoyl phosphotidylcholine at the 2-position to ¹⁴ C-palmiticacid) was quantitated in this assay. The reaction mixture contained Trisbuffer (25 mM0, pH 8.0, calcium chloride (2.0 mM), bovine serum albumin(0.5 mg), dipalmitoyl phosphotidylcholine (8×10⁻⁵ M), (¹⁴C-palmitoyl)dipalmitoyl phosphotidylcholine (6×10³ cpm), porcinepancreatic PLA₂ (3.2 units) and the test compound. The reaction was runat 37° C. in a shaking incubator. The reaction was quenched and aninternal standard was added in order to determine sample recovery. Thesamples were loaded onto D₁₈ columns, eluted with ethanol, and theradioactivity was then measured. (Standard: quinacrine IC₅₀₋₃.5×10⁻⁴ M).See Feyen, J. H. M. et. al., Journal of Chromatography 259 (1983), pp.338-340.

TPA-Induced Ear Edema (TPAEE)

The purpose of this assay was to determine the ability of atopically-applied compound to prevent ear edema induced by topicalapplication of TPA (phorbol 12/myristate acetate). Female Swiss WEbstermice topically received TPA (10μg/ear) on the right ear and vehicle onthe left ear. The test compound (10μg/ear) was applied to both ears.After five hours, the animals were sacrificed and an ear punch (4 mm)was taken from each ear. The difference in right and left ear punchweights for each animal was determined to uses activity. (Standard:hydrocortisone ED₅₀ =47 μg/ear). See Yound, J. M. et. al., J. Invest.Dermatol., 80 ( 1983), pp. 48-52.

Dermatological activities for some of the compounds of this inventionare presented in Table 1.

                  TABLE 1                                                         ______________________________________                                                        PIPE*     PLA.sub.2 *                                                                            TPAEE                                      Compound        (0.1 M)   (0.01 M) (10 μg)                                 ______________________________________                                        1-(4-Amino-3-   -33%      -85%     -35%                                       pyridinyl)-2,3-                                                               dihydro-1H-indole                                                             1-(3-Amino-4-   -34%      -42%     -74%                                       pyridinyl)-2,3-                                                               dihydro-1H-indole                                                             2-(4-Amino-3-   -42%      -59%     -45%                                       pyridinyl)-1,2,3,4-                                                           tetrahydroisoquinoline,                                                       N-oxide                                                                       ______________________________________                                         *difference in edema vs. control                                         

Examples of the compounds of this invention include:

1-(4-Amino-3-pyridinyl)-2,3-dihydro-01H-indole;

1-(3-Amino-4-pyridinyl)-2,3-dihydro-1H-indole;'

1-(4-Amino-3-pyridinyl)-1,2,3,4-tetrahydroquinoline;

2-(4-Amino-3-pyridinyl)-1,2,3,4-tetrahydroisoquinoline, N-oxide;

N-[3-(2,3-Dihydro-1H-indol-1-yl)pyridin-4-yl]acetamine;

2,3-Dihydro-1-(4-nitro-3-pyridinyl)-1H-indole,N-oxide;

2,3-Dihydro-1-(4-nitro-3-pyridinyl)-1H-indole;

1-(4-Nitro-3-pyridinyl)-1,2,3,4-tetrahydroquinoline, N-oxide;

2-(4-Nitro-3-pyridinyl)-1,2,3,4-tetrahydroisoquinoline, N-oxide;

1-(3-Methylamino-4-pyridinyl)-2,3-dfihydro-1H-indole;

1-(3-Benzylamino-4-pyridinyl)-2,3-dihydro-1H-indole;

2-(4-Amino-3-pyridinyl)-1,2,3,4-tetrahydroquinoline;

1-(4-Propylamino-3-pyridinyl)-1,2,3,4-tetrahydroquinoline; and

2-[3-(2-Phenylethyl)amnio-4-pyridinyl]-1,2,3,4-tetrahydroisoquinoline,N-oxide;

The followiing examples are presented in order to illustrate thisinvention:

EXAMPLE 1 2,3-Dihydro-1-(4-nitro-3-pyridinyl)-1H-indole, N-oxide

A solution of 3-fluoro-4-nitropyridein-N-oxide¹ (5 g) and indoline (4 g)in 100 ml ethanol was stirred for one hour at reflux and thereaftercooled and concentrated. The residue was purified by flashchromatography (silca, ethyl actate) to give 8 g solid, m.p. 168-170°.Four grams were recrystallized from ethanol to give 3 g needles, m.p.170-172°.

    ______________________________________                                         Analysis                                                                     ______________________________________                                        Calculated for C.sub.13 H.sub.11 N.sub.3 O.sub.3                                              60.69% C  4.31% H  16.34% N                                   Found           60.55% C  4.22% H  16.11% N                                   ______________________________________                                    

EXAMPLE 2 2,3-Dihydro-1-(3-nitro-4-pyridinyl)-1H-indole

To 50 ml ethanol were added 4-chloro-3-nitropyridine (10 g) andtriethylamine (8 ml) followed by a solution of indoline (7.0 ml) in 50ml ethanol.

After stirring at ambient temperature for one hour, a precipitate beganforming, and stirring was continued for five hours. The mixture waspoured into 500 ml water, the pH was adjusted to 10 with a Na₂ CO₃solution, and the resultant precipitate was collected, washed with etherand dried at 50° C. overnight in a vacuum oven to give 8.2 g solid, d @156-158° C. A 3.0 g sample of this material was recrystallized fromethanol/ether (1:1) to give a solid, 2.3 g, m.p. 159-160° C.

    ______________________________________                                         Analysis                                                                     ______________________________________                                        Calculated for C.sub.13 H.sub.11 N.sub.3 O.sub.2                                              64.72% C  4.60% H  17.42% N                                   Found           64.76% C  4.57% H  17.37% N                                   ______________________________________                                    

EXAMPLE 3 1-(4-Nitro-3-pyridinyl)-1,2,3,4-tetrahydroquinoline, N-oxide

To 100 ml of ethanol were added 3-fluoro-4-nitropyridine-N-oxide (7.0 g)and 1,2,3,4-tetrahydroquinoline (6.89 ml) and this mixture was heated to70° C. and stirred for 13 hours. The reaction mixture was then cooled,poured into water and extracted with ethyl acetate. The organic layerwas washed with water and dried (saturated NaCl, anhy. MgSO₄).

After filtration, the solvent was evaporated to yield a solid (12.0 g),which was eluted with 10% ethyl acetate/dichlorometahne (DCM) and thenwith ethyl acetate on a silica gel column via HPLC. The desiredfractions were concentrated to yield a solid (3.45 g). A 1.1 g samplewas recrystallized from methanol to yield a solid, 0.6 g, m.p. 171-173°C.

    ______________________________________                                         Analysis                                                                     ______________________________________                                        Calculated for C.sub.14 H.sub.13 N.sub.3 O.sub.3                                              61.98% C  4.83% H  15.49% N                                   Found           61.80% C  4.80% H  15.42% N                                   ______________________________________                                    

EXAMPLE 4 2-(4-Nitro-3-pyridinyl)-1,2,3,4-tetrahydroisoquinoline,N-oxide

To 100 ml of ethanol were added 3-fluoro-4-nitropyridine-N-oxide (7.0 g)and 1,2,3,4-tetrahydroisoquiniline (6.38 g) and the is mixture washeated to 60° C. and stirred for two hours. Filtration of the mixtureafforded a solid (11.2 g). Recrystallization of a 3.0 g portion of thismaterial yielded a solid, 2.2 g, m.p. 165-167° C.

    ______________________________________                                         Analysis                                                                     ______________________________________                                        Calculated for C.sub.14 H.sub.13 N.sub.3 O.sub.3                                              61.98% C  4.83% H  15.49% N                                   Found           62.14% C  4.91% H  15.54% N                                   ______________________________________                                    

EXAMPLE 5 1-(4-Amino-3-pyridinyl)-2,3-dihydro-1H-indole

A solution of 2,3-dihydro-1-(4-nitro-3-pyridinyl)-1H-indole, N-oxide(4.5 g) in 250 ml ethanol containing 0.5 g platinum oxide washydrogenated at 50 psi (pounds per square inch) for five hours andthereafter filtered and concentrated to an oil. This oil was purified byflash chromatography (silca, 10% methanol in dichlorometahne) to give 4g oil. This oil was converted to the hydrochloride salt anddecrystallized twice from ethanol/ether to give 3 g crystals, d 274°.

    ______________________________________                                         Analysis                                                                     ______________________________________                                        Calculated for C.sub.13 H.sub.13 N.sub.3 .HCl                                                  63.03% C 5.70% H  16.97% N                                   Found            62.96% C 5.64% H  16.81% N                                   ______________________________________                                    

EXAMPLE 6 1-(3-Amino-4-pyridinyl)-2,3-dihydro-1H-indole

In a 500 ml Parr hydrogenation bottle was suspended 1.0 g of 5% Pd/C in25 ml ethanol, followed by a suspension of2,3-dihdyro-1-(3-nitro-4-pyridinyl)-1H-indole (4.7 g) in 125 ml ethanol.After shaking at 50 psi H₂ p at ambient temperature for five hours themixture was filtered and the filtrate concentrated to an oil (4.2 g).This oil was eluted on a silica gel column with ethyl acetate via HPLCand the desired fraction were combined and concentrated to give a solid,4.0 g, m.p. 89-9° C. This material was recrystallized from ether/hexanes(4:1) to give solid, 2.9 g, m.p. 90-92° C.

    ______________________________________                                         Analysis                                                                     ______________________________________                                        Calculated for C.sub.13 H.sub.13 N.sub.3                                                     73.91% C 6.20% H    19.89% N                                   Found          74.08% C 6.30% H    19.94% N                                   ______________________________________                                    

EXAMPLE 7 1-(4-Amino-3-pyridinyl)-1,2,3,4-tetrahydroquinolinehydrochloride

To a slurry of PtO₂ (0.3 g) in 10 ml of ethanol was added1-(4-nitro-3-pyridinyl)-1,2,3,4-tetrahydroquinoline, N-oxide (2.5 g) in240 ml of ethanol and this was hydrogenated with a Parr apparatus atroom temperature for 48 hours. The mixture was then filtered and thefiltrate concentrated to yield an oil (2.5 g), which was eluted with 10%methanol/DCM on a silica gel column via HPLC. The desired fractions wereconcentrated to yield an oil (1.5 g). This material was converted to theHCl salt with ethereal HCl and the resulting solid (1.45 g) wasrecrystallized from methanol/ether (1:5) to yield a solid, 0.8 g,m.p.>270° C.

    ______________________________________                                         Analysis                                                                     ______________________________________                                        Calculated for C.sub.14 H.sub.15 N.sub.3 .HCl                                                  64.24% C 6.16% H  16.05% N                                   Found            64.12% C 6.10% H  15.85% N                                   ______________________________________                                    

EXAMPLE 8 2-(4-Amino-3-pyridinyl)-1,2,3,4-tetrahydroisoquinoline-N-oxide

To a slurry of PtO₂ (0.3 g) in 10 ml of ethanol was added2-(4-nitro-3-pyridinyl)-1,2,3,4-tetrahydroisoquinolein, N-oxide (5.0 g)in 240 ml of ethanol and this was hydrogenated with a Parr apparatus atroom temperature for 24 hours. The mixture was filterd and the filtrateconcentrated to yield an oil(5.1 g), which was eluted with 20%methanol/DCM on a silica gel column via HPLC. The desired fractions wereconcentrated to a solid (2.0 g), m.p. 216-219° C. (decomp). This solidwas recrystallized from acetonitirile to yield a solid, 1.0 g, m.p.217-219° C.

    ______________________________________                                         Analysis                                                                     ______________________________________                                        Calculated for C.sub.14 H.sub.15 N.sub.3 O                                                   69.69% C  6.27% H   17.42% N                                   Found          69.52% C  6.27% H   17.39% N                                   ______________________________________                                    

EXAMPLE 9 N-[3-(2,3-dihydro-1H-indol-1-yl)pyridin-4-yl]acetamide maleate

A solution of 1-(4-amino-3-pyridinyl)-2,3-dihydro-1H-indole (5 g) in 25ml acetic anhydride was stirred for one hour at ambient temperature andthereafter concentrated, stirred with water, gasified with sodiumcarbonate and extracted with ethyl acetate. The organic extract waswashed with water and saturated sodium chloride solution, dried (anhy.MgSO₄) filtered and concentrated to 7 g oil. This oil was purified byflash chromatography (silica, 20% ethyl acetate in dichloromethane) togive 5 g solid, m.p. 123-125°. This solid was converted to the maleatesalt in methanol/ether to give 5.6 g crystals, d 158-160°. A 2.5 gsample was recrystallized from methanol/ether to give 2.2 g crystals d160-161°.

    ______________________________________                                         Analysis                                                                     ______________________________________                                        Calculated for                                                                            61.78% C   5.18% H  11.38% N                                      C.sub.15 H.sub.15 N.sub.3 O.C.sub. 4 H.sub.4 O.sub.4                          Found       61.60% C   5.11% H  11.39% N                                      ______________________________________                                    

We claim:
 1. A compound having the formula, ##STR8## where R ishydrogen, loweralkyl, arylloweralkyl or loweralkylcarbonyl;k is 0 or 1;m is 1, 2 or 3; k+m is 2 or 3; and n is 0 or 1; or a pharmaceuticallyacceptable acid salt thereof.
 2. The compound as defined in claim 1,where R is hydrogen or loweralkylcarbonyl.
 3. The compound as defined inclaim 1, which is 1-(4-amino-3-pyridinyl)-2,3-dihydro-1H-indole.
 4. Thecompound as defined in claim 1, which is1-(3-amino-4-pyridinyl)-2,3-dihydro-1H-indole.
 5. The compound asdefined in claim 1, which is1-(4-amino-3-pyridinyl)-1,2,3,4-tetrahydroquinoline.
 6. The compound asdefined in claim 1, which is2-(4-amino-3-pyridinyl)-1,2,3,4-tetrahydroisoquinoline, N-oxide.
 7. Thecompound as defined in claim 1, which isN-[3-(2,3-dihydro-1H-indol-1-yl)pyridin-4-yl]acetamine.
 8. The compoundas defined in claim 1, which is1-(3-methylamino-4-pyridinyl)-2,3-dihydro-1H-indole.
 9. The compound asdefined in claim 1, which is1-(3-benzylamino-4-pyridinyl)-2,3-dihydro-1H-indole.
 10. The compound asdefined in claim 1, which is2-(4-amino-3-pyridinyl)-1,2,3,4-tetrahydroisoquinoline.
 11. The compoundas defined in claim 1, which is1-(4-propylamino-3-pyridinyl)-1,2,3,4-tetrahydroquinoline.
 12. Thecompound as defined in claim 1, which is2-[3-(2-phenylethyl)amino-4-pyridinyl]-1,2,3,4-tetrahydroquinoline,N-oxide.
 13. A dermatological composition which comprises a compound asdefined in claim 1 in an amount effective for treating a skin disorder,and a suitable carrier therefor.
 14. A method of treating a patient inneed of relief from a skin disorder which comprises administering tosuch a patient an effective amount of a compound as defined in claim 1.